tbuckley/cabot-search huggingface dataset:
Abstract 2506: The influence of sex on the immune microenvironment in male and female breast cancer
Authors: Ebony Hargrove-Wiley, Barbara Fingleton
Journal: Cancer Research (2023)

Abstract Even when accounting for multiple clinical parameters, male breast cancer patients have significantly lower survival rates than females. Males and females differ in their levels of sex hormones androgens and estrogens. These sex hormones have varying influences on immune cell populations, which in turn may affect disease progression. Thus, the sex of the patient and the levels of sex hormones are likely important for anticancer immunity. Here, we assessed the importance of sex hormone signaling in the immune cells (host) versus the tumor cells for defining the immune landscape associated with primary and metastatic tumors. We used flow cytometry to determine the immune profile of mammary tumors, spleens, and lungs, and histochemistry to evaluate metastasis in transgenic MMTV-PyMT and in mice orthotopically injected with sex-specific MMTV-PyMT-derived cell lines in male and female cohorts. In transgenic mice, males had greater proportions of CD4+ T-helper and total myeloid cells in all organs analyzed. The splenic and pulmonary immune profiles of tumor-bearing males were more similar to cancer-free littermates than in females. Interestingly, males trended towards increased metastatic colonization in the lungs. Sex-associated immune profiles differed between transgenic and orthotopic mice. In mice bearing male-derived R221a PyMT tumors, females had decreased intratumoral neutrophils and elevated natural killer cells with increased splenic B-cells in comparison to males. Overall, our data supports a sex-dependent immune response in mammary carcinoma that is, in part, regulated by the hormonal environment of the host. With emerging therapeutics targeting the tumor immune microenvironment, characterization of immune profiles is critical for optimizing their use in all breast cancer patients. Citation Format: Ebony Hargrove-Wiley, Barbara Fingleton. The influence of sex on the immune microenvironment in male and female breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2506.
Abstract 2634: AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion
Authors: Byeongkwi Min, Lily Shi, Hye Jin Kim, Sangwoo Kim, Beibei Fan, Cao Lv, Yajun Sun, Nam-Gu Her, Paul Song, Gang Qin, Do-Hyun Nam
Journal: Cancer Research (2023)

Abstract Background: FGFR3-TACC3 (F3-T3) fusion leads to FGFR3 kinase activation constitutively and acts as a driver mutation in several solid tumors. AMB302/GR1017 is a novel FGFR3 targeting ADC that was developed using the intelligent Ligase-Dependent Conjugation (iLDC) technologies from GeneQuantum (GQ) that provide high homogeneity, excellent druggability and high linker stability, and contains a topoisomerase 1 inhibitor as a payload. Based on the preclinical characterization, AMB302/GR1017 shows impressive anti-tumor activities against glioblastoma (GBM) and bladder cancer (BC) models with either FGFR3 amplification or F3-T3 fusion, and demonstrates the potential as a first-in-class FGFR3 ADC against FGFR3 active solid tumor indications. Methods: in vitro anti-tumor effects and mechanism of action for AMB302/GR1017 were assessed on patients-derived cells with F3-T3 using a 3D-spheroid high throughput assay. in vivo anti-tumor effect of AMB302/GR1017 were assessed on F3-T3 fusion GBM orthotopic PDX model and several FGFR3+ or F3-T3 fusion BC models Results: AMB302/GR1017 was generated by linking FGFR3 targeting antibody (AimedBio) with TopoIx (GQ), a next generation Topoisomerase 1 inhibitor via a cleavable linker using the iLDC technologies. In a 3D-spheroid high throughput assay system, AMB302/GR1017 showed significant anti-tumor activity against glioblastoma patients-derived cells (PDCs) in F3-T3 dependent manner, which is superior to chemical conjugate applying the same antibody and Dxd payload. Also, AMB302/GR1017 prolonged the survival of GBM orthotopic PDX models with F3-T3 fusion by 200 % and achieved complete tumor regression in RT112 BC model with F3-T3 fusion. AMB302/GR1017 treatments were well-tolerated up to 200 mg/kg in a mouse safety study. Conclusion: AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations. Citation Format: Byeongkwi Min, Lily Shi, Hye Jin Kim, Sangwoo Kim, Beibei Fan, Cao Lv, Yajun Sun, Nam-Gu Her, Paul Song, Gang Qin, Do-Hyun Nam. AMB302/GR1017, an antibody-drug conjugate (ADC) with topoisomerase 1 inhibitor shows therapeutic potency in orthotopic glioblastoma PDX and bladder cancer models with FGFR3-TACC3 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2634.
Abstract 677: Increasing plexity of imaging mass cytometry for tumor tissue analysis
Authors: Thomas D. Pfister, Shaida Ouladan, Huihui Yao, Daniel Majonis, Christina Loh, Nick Zabinyakov
Journal: Cancer Research (2023)

Abstract Imaging Mass Cytometry™ (IMC™) is the leading platform for high-plex tissue imaging. IMC allows for detailed assessment of cell phenotype and function using 40-plus markers simultaneously at subcellular resolution on a single slide. A comprehensive IMC panel containing structural, functional, and immune markers enables us to reveal the complex heterogeneity of tumor tissues as well as the tumor microenvironment (TME). Driven by an increase in the number of antibody markers and the addition of mRNA markers, there is an increasing demand for larger panels. In addition, increasing the number of investigated target markers on a single tissue enriches spatial characterization that may facilitate a more accurate prediction of disease progression and preclinical outcome measures in clinical research projects using tumor biopsies or tissue microarrays (TMAs). Therefore, to increase the plexity of IMC panels, it is essential to expand the number of available metal channels. Here, we demonstrate the incorporation of conjugated antibodies with yttrium (89Y) and indium (115In), two low-mass metals, for IMC application. These metal tags have been previously tested as putative channels for IMC application. We performed IMC analysis of various tissue types stained with panels of conjugated antibodies including the novel 89Y- and 115In-conjugated antibodies. At least 3 different regions of interest (ROIs) were assessed for each of the investigated tissue types. We compared images for the 89Y- and 115In-conjugated antibodies with the images generated using Maxpar® catalog antibodies of the same clones, with a focus on marker specificity and background signal. Compared with the lanthanide-conjugated catalog antibodies, the 89Y- and 115In-conjugated antibodies showed equivalent specificity and staining quality. Our results open a new avenue to assign markers to 89Y and 115In, which enables a larger list of potential targets to be investigated in any IMC study. Expanding the number of markers to 40-plus in Imaging Mass Cytometry will improve the imaging results necessary to identify novel cell signatures (phenotype and interactions) in the TME. Citation Format: Thomas D. Pfister, Shaida Ouladan, Huihui Yao, Daniel Majonis, Christina Loh, Nick Zabinyakov. Increasing plexity of imaging mass cytometry for tumor tissue analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 677.
Abstract 5218: Genome-wide association study of African Americans reveals new susceptibility loci contributing to lung cancer and mechanisms of population-specific etiology
Authors: Jinyoung Byun, Younghun Han, Xiangjun Xiao, Christine Lusk, Hoda J. Badr, Rayjean Hung, Ann G. Schwartz, Christopher I. Amos
Journal: Cancer Research (2023)

Abstract Lung cancer incidence and mortality in the U.S. have substantial ethnic disparities. African Americans of both sexes have the high incidence rate at 56.8 and the highest death rate at 38.1 per 100,000 people from 2015 to 2019. Non-Hispanic black men have the highest incidence at 73.9 and the highest death rate at 56.3 per 100,000 people. While many genome-wide association studies (GWAS) of lung cancer have discovered ~45 putative risk loci, a large proportion of the heritability of lung cancer remains unexplained. To date, most single population-based GWAS have been performed in Europeans while there are a few Asian ancestry-specific genetic studies and two cross-ancestry studies. Non-European GWAS of lung cancer has been underrepresented. Although African Americans have higher lung cancer incidence and poorer lung cancer survival rate, and smoke fewer cigarettes per day compared to Europeans, few comprehensive GWAS of lung cancer in African Americans has been conducted. This study aims to decipher the genetic component of predisposition to lung cancer among African Americans. This study aims to decipher the genetic component of predisposition to lung cancer among African Americans. We conducted an African-ancestry GWAS comprising 2,280 lung cancer cases and 4,301 controls to comprehensively characterize common and low-frequency lung cancer genetic susceptibility loci using HRC imputed lung cancer data. The novel variants in or near VWF on 12p13.31 (OR=1.29, P=6.93 × 10−9) for overall lung cancer and GACAT3 on 2p24.3 (0.65, 1.24 × 10−9), TRIP13 on 5p15.33 (3.49, 1.00 × 10−8), ERC1 on 12p13.33 (4.64, 6.08 × 10−9), LMAN1L (near CYP1A1) on 15q24.1 (4.25, 8.71 × 10−9) for lung squamous cell cancer were identified at a genome-wide significance level. Our GWAS of lung cancer identified five novel genetic susceptibility associations and confirmed several variants on 15q25 and 19q13. Further works are required to elucidate the possible biological mechanisms underlying these associations among lung cancer and histological subtypes in African Americans. Citation Format: Jinyoung Byun, Younghun Han, Xiangjun Xiao, Christine Lusk, Hoda J. Badr, Rayjean Hung, Ann G. Schwartz, Christopher I. Amos, INTEGRAL Consortium. Genome-wide association study of African Americans reveals new susceptibility loci contributing to lung cancer and mechanisms of population-specific etiology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5218.
Abstract 458: Targeting p27Kip1 to inhibit CDK4/6/2 as a novel therapeutic strategy to treat pancreatic ductal adenocarcinoma
Authors: Carolina Guido, Susan RS Gottesman, Stacy W. Blain
Journal: Cancer Research (2023)

Abstract CDK4/6 inhibitors are powerful tools used clinically to treat metastatic, HR+ BC patients. While combined CDK4/6i treatment in combination with Estrogen modulation significantly extends Progression Free Survival (PFS) in metastatic HR+ breast cancer patients, those treated invariably develop aquired resistance, which results in only marginal improvement in Overall Survival (OS). The drug resistance seen in the presence of CDK4/6i, such as palbociclib, has been shown to be attributed to activation and compensation by CDK2. Pancreatic ductal adenocarcinoma (PDAC) is characterized by aberrant activation of the CyclinD-CDK4/6 signaling pathway and inactivation of the CDKN2A locus encoding the CDK4/6 inhibitor, p16INK4A, and was initially thought to be a good candidate for CDK4/6i use. Surprisingly, CDK4/6i do not show response in most PDAC lines and have not been used clinically in this tumor type. We hypothesized that PDAC may be intrinsically resistant to CDK4/6 inhibition due to activation of CDK2 and as such inhibition of both CDK4/6 and CDK2 may be required. We have developed a novel strategy to kill drug-resistant tumor cells using a therapeutic liposomal:peptide formulation, IpY.1, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. IpY.1 is specific for p27, and this reduces toxicity relative to that seen with the small molecule ATP-competitive CDK4/6i or CDK2i. IpY.1 blocks DNA replication in HR+ breast cancer (BC) cells and mouse models, but unlike CDK4/6i or CDK2i treatment, it induces ROS-dependent necroptosis to kill the tumor cells. Palbociclib did not have a significative effect on ATP levels or proliferation of PDAC cell lines. In contrast, we found that IpY.1 was able to block proliferation and reduce viability in palbociclib-resistant PDAC lines, suggesting that dual CDK4/6 and CDK2 inhibition via p27 targeting was required. Some PDAC lines were “super sensitive” and responded with IC50 values ~10X less than seen with the ER+ BC lines, and we are currently screening for biomarkers of response. CDK2 activity was reduced in IpY.1 treated lines and markers of necroptosis were detected. Immunoblot analysis showed decreased pY88 phosphorylation of p27 (the target of IpY) demonstrating target engagement. We have demonstrated that unlike palbociclib, IpY.1 blocks proliferation and viability in all PDAC lines tested, suggesting that targeting p27 may be a viable approach to treat PDAC. Citation Format: Carolina Guido, Susan RS Gottesman, Stacy W. Blain. Targeting p27Kip1 to inhibit CDK4/6/2 as a novel therapeutic strategy to treat pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 458.
Abstract 338: Regulation of gap junction intercellular communication in pancreatic cancer cells
Authors: Annelise Nguyen, My Doan
Journal: Cancer Research (2023)

Abstract According to the American Cancer Society, approximately 62,210 people (32,970 men and 29,240 women) in the United States are estimated to be diagnosed with pancreatic cancer by the end of 2022. An estimated 80% of these patients will die as a result of pancreatic cancer. This type of cancer has been challenging to treat due to the complexity of tumor cells, tumor aggressiveness, current drug availability, and drug delivery. A new class of substituted quinolines, known as PQ compounds, acts as gap junction enhancer, having the ability to increase the gap junctional intercellular communication cancerous cells. The goal of this project is to provide a new approach to treat pancreatic cancer via restoration of gap junctional intercellular communication and combining treatment with antineoplastic drugs. One approach was to increase cell communication of pancreatic cancer cells using small molecules, PQs, and hence allowing antineoplastic drugs to effectively travel from cell to cell. Pancreatic cancer cells were treated with gap junction enhancers, PQs, in the presence and absence of antineoplastic drugs. Interestingly, 5-FU significantly decreased the expression of gap junction protein, connexin 43, compared to control and PQ1 treatments. PQ1 has demonstrated to increase Cx43 expression and increase 4.5-fold of gap junction activity. Furthermore, cells treated with nilotinib have a significant effect on PANC-1 cells. Current studies focus on functional assays to determine if PQ1 can increase cell-cell communication, allowing a reduced concentration of antineoplastic drugs to be used. Overall, the findings provide an initial insight to a new approach in treating pancreatic cancer. Citation Format: Annelise Nguyen, My Doan. Regulation of gap junction intercellular communication in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 338.
Abstract 767: Genomics and transcriptomics profiling of BRCA mutation carriers revealed the landscape of early pathogenesis of BRCA1/2-associated breast cancer
Authors: Zuen Ren, Po-Han Lin, Siang Boon Koh, Kai Stewart, Nick Haradhvala, Aylin S Dedeoglu, Ilze Smidt, Akiko Suzuki, David Li, Win Thant, Sarah Mueller, Taisha Joseph, Veerle Bossuyt, Michael Lawrence, Gad Getz, Leif W. Ellisen
Journal: Cancer Research (2023)

Abstract Women who harbor germline heterozygous mutations of BRCA1 or BRCA2 have a high risk of breast cancer. Our previous study showed that patient-derived, ostensibly normal BRCA2mut/+ luminal progenitor (LP) cells are more prone to exhibit sub-chromosomal copy number variations and associated DNA damage relative to non-carriers potentially reflecting early breast tumorigenesis. The clinically assessable biomarkers for early pathological changes of BRCA1/2 mutation in LP cells remain unknown. Single-cell RNA sequencing (scRNAseq) of LP cells of BRCA1/2 mutation carriers revealed enrichment of KIT expression (KIT+) and subsequent transcriptional factor activations were observed in LP cells of BRCA1/2 mutation carriers relative to non-carriers. Moreover, overrepresented pathway analysis uncovered that KIT+ BRCA-mutated LP cells were enriched in pathways involving DNA binding transcription activator activity and oxidative phosphorylation. These gene signature profiles were recapitulated in bulk RNA-seq of BRCA2 mutation carrier LP cells. Collectively, our preliminary data suggest such analyses may identify potential biomarkers of the risk prediction for early pathogenesis of BRCA1/2 mutation carriers. Following validation of our findings via tissue microassay analysis and clinical trials, we hope to eventually assist clinicians in their decision making of prophylactic surgeries for BRCA1/2 mutation carriers. Citation Format: Zuen Ren, Po-Han Lin, Siang Boon Koh, Kai Stewart, Nick Haradhvala, Aylin S Dedeoglu, Ilze Smidt, Akiko Suzuki, David Li, Win Thant, Sarah Mueller, Taisha Joseph, Veerle Bossuyt, Michael Lawrence, Gad Getz, Leif W. Ellisen. Genomics and transcriptomics profiling of BRCA mutation carriers revealed the landscape of early pathogenesis of BRCA1/2-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 767.
Abstract 1292: CX3CR1 surface expression and phenotypic plasticity in metastasis-initiating cells
Authors: Jieyi Zhang, Yetunde Oyende, Jennifer Lynch, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2023)

Abstract Metastasis-initiating cells (MICs) display stem cell-like features and cause metastatic recurrences leading to patients' demise. We found that prostate and breast cancer cells with high surface expression of the chemokine receptor CX3CR1 (CX3CR1high) account for ~5-7% of the whole population and are endowed with metastasis-initiating ability and exhibits stemness features, including expression of pluripotency genes Nanog and Oct4a. Notably, impairing CX3CR1 signaling hinders metastatic initiation and progression in mouse models of human disease. We also found that cancer cells lacking surface CX3CR1 expression (CX3CR1low) can re-acquire CX3CR1-associated features over time by undergoing phenotypic plasticity. Accordingly, when grafted as pure CX3CR1low populations these cells could generate disseminated tumors in mice, implying that MICs can emerge from cancer cells lacking stemness features. In vitro studies by flow cytometry show that cell surface re-exposure of CX3CR1 by CX3CR1low cells begins within 2 days post-sorting, with the whole population reaching phenotypic equilibrium at 12-16 days post-sorting. Further mechanistic studies revealed that both CX3CR1 protein trafficking and transcriptional regulation play a role in phenotypic plasticity. Additionally, disseminated tumors in mice harbor higher percentages of CX3CR1high cells than in vitro cultures, suggesting that the tissue microenvironment of target organs promotes phenotypic plasticity. These findings nominate CX3CR1 as a novel marker of MICs and provide conceptual ground for future development of approaches targeting CX3CR1 signaling and (re)expression as therapeutic means to prevent or contain metastasis initiation and progression. Citation Format: Jieyi Zhang, Yetunde Oyende, Jennifer Lynch, Olimpia Meucci, Alessandro Fatatis. CX3CR1 surface expression and phenotypic plasticity in metastasis-initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1292.
Abstract 1915: Cancer disparities in the University of Chicago Comprehensive Cancer Center Catchment Area
Authors: Stephanie Zhang, Joel Ssepuuya, Brandon Pierce
Journal: Cancer Research (2023)

Abstract Disparities in cancer incidence and mortality have not been described for the University of Chicago Comprehensive Cancer Center’s patient catchment area (CA), the region from which the center draws its patients. The purpose of this research was to describe incidence and mortality rates (2013-2017) for leading cancers in the CA, which consists of Cook County, IL; DuPage County, IL; Lake County, IL; Will County, IL; and Lake County, IN. Age-adjusted rates (per 100,000) were calculated for leading cancers by sex for each county, the CA, U.S., and IL. Racial disparities were also examined by comparing Black rates to White rates. Incidence rates were higher in the CA compared to the U.S for all cancers data was available for: all sites combined, breast, and prostate. For males, mortality rates of prostate, colorectal, pancreatic, and stomach cancers were higher in the CA compared to the U.S. For females, mortality rates of breast, colorectal, myeloma, uterine, stomach, and bladder cancers, as well as all sites combined were higher in the CA compared to the U.S. By county, males experienced incidence rates 8% to nearly 2.5 times higher and mortality rates 3% to over 1.5 times higher compared to the U.S. for various cancers. By county, females experienced incidence rates 5% to over 4 times higher and mortality rates 4% to over 1.5 times higher compared to the U.S. for various cancers. Lake County, IN generally had the highest incidence and mortality rates. Racial disparities in incidence and mortality were present for most cancers in the CA overall and by county. For males, racial disparities in mortality for prostate, stomach, and larynx are of greatest concern. For females, racial disparities in mortality for myeloma, cervical, and uterine are of greatest concern. This research highlights important health inequities and priorities for the UChicago Cancer Center. Citation Format: Stephanie Zhang, Joel Ssepuuya, Brandon Pierce. Cancer disparities in the University of Chicago Comprehensive Cancer Center Catchment Area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1915.